This revised application is aimed at developing and validating positron labeled ligands for the beta-adrenergic receptor with suitable binding characteristics to measure the receptor concentration and association constant in vivo. The ligands will measure the total receptors, those on the cell surface and the beta1 and beta2 sub-types. A series of ligands, labeled with the short lived positron emitting radionuclide fluorine-18, will be synthesized and their kinetic receptor binding properties examined in: S49 cells, the isolated rat heart and finally in dogs using positron imaging techniques. Developing a labeled ligand to study the beta-adrenergic system in vivo has proved difficult. Ligands which work well in vitro do not show receptor mediated binding in vivo. Others, with smaller equilibrium dissociation constants have shown receptor mediated binding that is largely independent of receptor concentration. The data obtained from our ligands will be modeled using both compartmental and distributed physiological models and examined for sensitivity to the receptor concentration. This data will be correlated to the partition coefficient (lipophillicty) of the ligand (how it is delivered from the blood to the tissues) and the association and dissociation rates, (k/on and k/off). These data will then be used to prepare modified ligands in which the lipophillicity and the association rates will be modified to more closely fit the ideal until a satisfactory agent has been obtained. The synthesis of a range of ligands will be straightforward as general methods for preparing most of the labeled beta-adrenergic ligands have already been developed. Some understanding of the molecular characteristics that control the way the ligands bind to the beta-receptor has been acquired and this, in combination with modern computational techniques, will shorten the path that must be followed to develop the optimum ligand. Beta-Adrenergic receptors play an essential role in the regulation and control of the heart and abnormalities in the beta-adrenergic systems are thought to be involved in a number of heart diseases. These include sudden death, arrhythmia's and congestive and ischemic heart failure. Antagonists for the beta- receptor system 'beta-blockers' are the most widely prescribed drugs in the treatment of heart disease. However our knowledge of the role these receptors play in disease states is limited by our ability to measure them in vivo. The successful outcome of this work will be a method that permits the measurement of the beta-adrenergic receptor in vivo in humans in a sequential fashion that can be used to select and monitor therapies in patients with diseases involving the beta-adrenergic receptor system.